spa-aap reviews
Sunday Session II: Presentations by the three 2016 SPA Young Investigator Research Award Recipients
Reviewed by Cornelius Groenewald, MD
Seattle Children’s Hospital and University of Washington
Effects of Obesity, OSA, Leptin, and Inflammatory Cytokines on Morphine Pharmacokinetics in Children
Nicholas M Dalesio, MD; Johns Hopkins University School of Medicine
Mentor: Robert H. Brown, MD, MPH
Dr. Nicholas Dalesio MD, at Johns Hopkins University, studies the relationship between obesity, obstructive sleep apnea (OSA), and morphine metabolism. Obesity and OSA are independent risk factors for post-operative respiratory complications; however underlying mechanisms are as yet unknown. Dr. Dalesio hypothesized that metabolic changes induced by obesity and OSA alters morphine pharmacokinetics. Furthermore, these alterations in morphine pharmacokinetics result in decreased morphine metabolism and excretion of its metabolites, increasing the risk for opioid-induced respiratory complications.
To address these hypotheses Dr. Dalesio performed a prospective observational cohort study enrolling four groups of surgical patients: group A consisted of normal weight children without OSA; group B consisted of obese children without OSA; group C consisted of normal weight children with OSA; and group D consisted of obese children with OSA. All children were 5-12 years old undergoing elective surgery. To measure morphine pharmacokinetics, all children had serial blood draws in the perioperative period for levels of morphine, morphine 3-glucuronide, and morphine 6-glucuronide. Dr. Dalesio’s main finding was that morphine metabolism was significantly different between groups A and C indicating that OSA, by itself, negatively affects morphine metabolism.
Therefore, the main conclusion was that OSA increases exposure to the morphine and its metabolites increasing the risk for opioid-induced complications. In future, Dr. Dalesio is enrolling more participants in order to also address whether a concomitant diagnosis of obesity may alter these changes in morphine pharmacokinetic.
Mechanisms for Ventricular Septation
Irfan Kathiriya, MD, PhD; University of California, San Francisco
Mentor: Benoit G. Bruneau, PhD
Dr. Irfan Kathiriya, at the Gladstone Institutes and the University of California, San Francisco, studies the causes of ventricular septal defects (VSDs) during development. VSDs are the most common lesions of congenital heart disease and can lead to heart failure and pulmonary hypertension. However, the cellular origins of VSDs are unknown. Thus, by better understanding the cellular mechanisms that underlie VSDs, Dr. Kathiriya hopes to discover new therapeutic targets for congenital heart disease.
To identify early precursor cells that contribute to the interventricular septum (IVS), Dr. Kathiriya, with Dr. W. Patrick Devine and Dr. Benoit Bruneau, genetically marked cells with a fluorescent protein in the developing mouse embryo. In this way, they identified early precursor cells that would later become IVS cells during embryogenesis. Interestingly, they found that cells from both ventricles contribute to the IVS. They selectively ablated these IVS precursor cells with diphtheria toxin, which caused severely abnormal ventricular septation, supporting that these IVS precursors are required for heart development. They also discovered that these early precursor cells express the gene Tbx5, which is associated with VSDs in humans. Reducing the gene dosage of Tbx5 led to VSD formation, further supporting that Tbx5 regulates ventricular septation.
In summary, Dr. Kathiriya shared his data describing the morphologic and genetic phenotypes of progenitor cells that contribute to ventricular septation. Future data from this area of research may reveal potential mechanisms for intervention or prevention of congenital heart disease.
Development and validation of a prediction tool for adverse postanesthetic outcomes in pediatric tonsillectomy
Rajeev Subramanyam, MD, MS; Cincinnati Children’s Hospital Medical Center
Mentor: Anna M. Varughese, MD, MPH
Co-Mentors: Senthil Sadhasivam, MD, MPH; Joel Tsevat, MD, MPH; Robert Coghill, PhD; Mark Eckman, MD, MS
Dr. Raj Subramanyam, at Cincinnati Children’s Hospital, is focused on developing prediction tools to identify children at high risk following tonsillectomy. To advance this goal, the main aim of the study he presented was to identify patients at high risk for adverse events following tonsillectomy. Specifically, he hypothesized that clinical, health system, and social factors all affect rates of adverse events following tonsillectomy.
To address this aim Dr. Subramanyam performed a single center prospective observational study of 1986 children undergoing tonsillectomy in an ongoing study. His team collected preoperative, anesthetic and adverse events data up to three weeks after surgery. The main outcomes of interest were rates of prolonged PACU stay, and post-discharge hospital visits up to three weeks following surgery.
Preliminary findings included that 13% of patients had severe adverse events up to three weeks following tonsillectomy, including bleeding, dehydration, nausea, and pain. In multivariate analysis, the use of dexamethasone was found to be protective for three-week adverse events.
A future direction of Dr. Subramanyam’s work includes development and validation of robust prediction models for patients at high risk following tonsillectomy.
